The hypothesis is that individuals carrying mutations in the genes coding for antioxidant enzymes will be predisposed to diseases whose pathogenesis is associated with an unbalanced production of oxygen radicals. The overall goal of this grant is to define the critical role of each antioxidant enzyme and the balance among antioxidant enzymes in pulmonary defense against oxidant injury. There are two aims. The first is to generate mouse models deficient for four antioxidant enzymes: CuZnSOD, MnSOD, GSHPx and catalase. Mice heterozygous for the targeted mutations will be used in breeding to determine the feasibility of generating homozygous knockout mice. Pathological studies will look for potential gross or subtle abnormalities in the genetically mutated mice. RNA and protein content for each of the antioxidant enzymes will be measured in various tissues including lung of normal heterozygous and homozygous mice. The second aim is to define biochemically and morphologically whether deficiencies in the antioxidant enzymes will render animals more susceptible to lung injury induced by hyperoxia, bleomycin, and asbestos.